The present invention relates to new aryl or heteroaryl quinolylphosphonic acid compounds, and to compositions containing them.
The prior art describes compounds that are capable of countering the excitatory and toxic effects of the excitatory amino acids (EAA) by blocking the initial activation of the AMPA (xcex1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptor (EP 0 640 612). Their usefulness is accordingly recognised for inhibiting pathological phenomena, especially neurotoxic phenomena associated with hyperactivation of the neurotransmission paths to the excitatory amino acids.
The Applicant has discovered new compounds of novel structure that have more powerful non-NMDA antagonist properties than do the compounds of the prior art. The compounds are therefore new and are potential powerful therapeutic agents for the acute, and also chronic, treatment of neurological and psychological disorders involving those amino acids, for example degenerative disorders such as cerebrovascular accident, cerebral or spinal traumatism, epilepsy, chronic neurodegenerative diseases such as Alzheimer""s disease, schizophrenia, lateral amyotrophic sclerosis or Huntington""s chorea.
The present invention relates more especially to compounds of formula (I): 
wherein:
R1 represents a halogen atom or a trifluoromethyl group,
R2 represents an aryl or heteroaryl group,
R3 and R4, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, aryl or arylalkyl group or a group 
(wherein R5 and R6, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl or aryl group),
it being understood that:
xe2x80x9calkylxe2x80x9d is understood to mean a linear or branched alkyl group containing from 1 to 6 carbon atoms,
xe2x80x9ccycloalkylxe2x80x9d is understood to mean a cyclic alkyl group containing from 3 to 8 carbon atoms,
xe2x80x9carylxe2x80x9d is understood to mean the groups phenyl, naphthyl or biphenyl, it being possible for those groups to be unsubstituted or substituted by from 1 to 3 groups selected from alkyl, cycloalkyl, alkoxy, polyhaloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, SO2NR7R8 (wherein R7 and R8, which may be identical or different, represent a hydrogen atom or an alkyl, cycloalkyl or aryl group) and halogen atoms,
xe2x80x9cheteroarylxe2x80x9d is understood to mean any mono- or bi-cyclic aromatic group containing from 5 to 10 ring atoms and containing from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur, it being possible for the heteroaryl to be attached to the benzene ring that carries it by a carbon atom or by a nitrogen atom when it has one, and for it to be unsubstituted or substituted by from 1 to 3 groups selected from alkyl, cycloalkyl, alkoxy, polyhaloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, SO2NR7R8 (wherein R7 and R8 are as defined hereinbefore) and halogen atoms,
their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred compounds of the invention are compounds of formula (I) wherein R1 represents a chlorine atom or a group CF3.
The preferred groups R2 are phenyl, naphthyl or biphenyl, those groups being unsubstituted or substituted, more especially by a halogen atom or by a group CF3, NO2, alkyl or SO2NH2, or pyrrole or thiophene groups.
More preferably, the invention relates to compounds of formula (I) wherein R3 and R4 simultaneously represent a hydrogen atom.
More especially still, the invention relates to compounds of formula (I) which are:
{7-chloro-2-oxo-6-[4-(trifluoromethyl)phenyl]-1,2-dihydro-3-quinolyl}-phosphonic acid
[7-chloro-6-(4-methylphenyl)-2-oxo-1,2-dihydro-3-quinolyl]phosphonic acid.
The invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (II): 
wherein R1 is as defined for formula (I),
which is condensed, in the presence of a base, such as, for example, pyridine, with a compound of formula (III): 
to yield a compound of formula (IV): 
wherein R1 is as defined hereinbefore,
which is cyclised in the presence of a catalytic amount of piperidine to obtain a compound of formula (V) 
wherein R1 is as defined hereinbefore,
which is subjected to a mixture of nitric acid and sulphuric acid to yield a compound of formula (VI): 
wherein R1 is as defined hereinbefore,
which is reduced using palladium-on-carbon in the presence of hydrogen or iron in a dilute alcoholic medium to yield a compound of formula (VII): 
wherein R1 is as defined hereinbefore,
which is converted by the action of NaNO2 and HBF4 to the corresponding diazonium fluoroborate salt of formula (VIII): 
wherein R1 is as defined hereinbefore,
which is condensed in the presence of palladium with a boronic acid compound of formula (IX): 
wherein Rxe2x80x22 represents an aryl or heteroaryl group as defined for formula (I), the heteroaryl group being attached to the boron atom by a carbon atom,
to yield a compound of formula (I/a), a particular case of the compounds of formula (I): 
wherein R1 and Rxe2x80x22 are as defined hereinbefore,
or which compound of formula (VII) is subjected to the action of 2,5-dimethoxytetrahydrofuran to yield a compound of formula (I/b), a particular case of the compounds of formula (I): 
wherein R1 is as defined hereinbefore,
which compounds of formulae (I/a) and (I/b) may be partially or totally deprotected in the presence of, for example, trimethylsilane bromide to yield a compound of formula (I/c), a particular case of the compounds of formula (I): 
wherein R1 and R2 are as defined hereinbefore and Rxe2x80x2 represents a hydrogen atom or an ethyl group,
which may be condensed with a compound of formula (X):
Rxe2x80x3xe2x80x94Clxe2x80x83xe2x80x83(X)
wherein Rxe2x80x3 represents an alkyl, aryl or arylalkyl group or a group 
(wherein R5 and R6 are as defined hereinbefore), to obtain a compound of formula (I/d), a particular case of the compounds of formula (I): 
wherein R1, R2, R3 and Rxe2x80x3 are as defined hereinbefore,
which compounds of formulae (I/a) to (I/d) constitute the totality of the compounds of formula (I), and can be purified according to a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base, and separated, where appropriate, into their isomers according to a conventional separation technique.
The compounds of the invention have very valuable pharmacological properties since they are powerful inhibitors of the AMPA receptor, and they are moreover selective since they do not affect the NMDA receptor and therefore do not have any of the side-effects described for NMDA antagonists. The use of those compounds as inhibitors of pathological phenomena associated with hyperactivation of the neurotransmission paths to the excitatory amino acids will therefore be particularly appreciated in the acute, and especially chronic, treatment of neurological and psychological disorders involving those amino acids, for example degenerative disorders such as cerebrovascular accident, cerebral or spinal traumatism, epilepsy, chronic neurodegenerative diseases such as Alzheimer""s disease, schizophrenia, lateral amyotrophic sclerosis or Huntington""s chorea.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) alone or in combination with one or more pharmaceutically acceptable excipients.
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration and especially tablets or dragees, sublingual tablets, sachets, paquets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels and drinkable or injectable ampoules.
The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or any associated treatments and ranges from 50 mg to 10 g per 24 hours in 1 or more administrations.